In vivo delivery of CRISPR-Cas9 using lipid nanoparticles enables antithrombin gene editing for sustainable hemophilia A and B therapy

Jeong Pil Han, Min Jeong Kim, Beom Seok Choi, Jeong Hyeon Lee, Geon Seong Lee, Michaela Jeong, Yeji Lee, Eun Ah Kim, Hye Kyung Oh, Nanyeong Go, Hyerim Lee, Kyu Jun Lee, Un Gi Kim, Jae Young Lee, Seokjoong Kim, Jun Chang, Hyukjin Lee, Dong Woo Song, Su Cheong Yeom

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Hemophilia is a hereditary disease that remains incurable. Although innovative treatments such as gene therapy or bispecific antibody therapy have been introduced, substantial unmet needs still exist with respect to achieving long-lasting therapeutic effects and treatment options for inhibitor patients. Antithrombin (AT), an endogenous negative regulator of thrombin generation, is a potent genome editing target for sustainable treatment of patients with hemophilia A and B. In this study, we developed and optimized lipid nanoparticles (LNPs) to deliver Cas9 mRNA along with single guide RNA that targeted AT in the mouse liver. The LNP-mediated CRISPR-Cas9 delivery resulted in the inhibition of AT that led to improvement in thrombin generation. Bleeding-associated phenotypes were recovered in both hemophilia A and B mice. No active off-targets, liver-induced toxicity, and substantial anti-Cas9 immune responses were detected, indicating that the LNP-mediated CRISPR-Cas9 delivery was a safe and efficient approach for hemophilia therapy.

Original languageEnglish
Article numbereabj6901
JournalScience Advances
Volume8
Issue number3
DOIs
StatePublished - Jan 2022

Fingerprint

Dive into the research topics of 'In vivo delivery of CRISPR-Cas9 using lipid nanoparticles enables antithrombin gene editing for sustainable hemophilia A and B therapy'. Together they form a unique fingerprint.

Cite this